Abstract
BackgroundIn recent years, PD-1/PD-L1 immune checkpoint inhibitors have improved cancer therapy in many tumor types, but no benefit of immune checkpoint therapy has been found in glioblastoma multiforme (GBM). Based on the results of our earlier work, which showed a reduction of PD-L1 expression in patients treated with temozolomide (TMZ), we aimed to investigate the link between TMZ therapy and the immune control point target PD-L1.MethodsRNA-sequencing data from de-novo and recurrent glioblastoma were analyzed by AutoPipe algorithm. Results were confirmed either in a cell model by two primary and one established GBM cell line and specimens of de-novo and recurrent GBM. PD-L1 and pathway activation of the JAK/STAT pathway was analyzed by quantitative real-time PCR and western blot.ResultsWe found a significant downregulation of the JAK/STAT pathway and immune response in recurrent tumors. The cell model showed an upregulation of PD-L1 after IFNγ treatment, while additional TMZ treatment lead to a reduction of PD-L1 expression and JAK/STAT pathway activation. These findings were confirmed in specimens of de-novo and recurrent glioblastoma.ConclusionsOur results suggest that TMZ therapy leads to a down-regulation of PD-L1 in primary GBM cells. These results support the clinical findings where PD-L1 is significantly reduced in recurrent GBMs. If the target is diminished, it may also lead to impaired efficacy of PD-1/PD-L1 inhibitors such as nivolumab.
Highlights
In recent years, PD-1/PD-L1 immune checkpoint inhibitors have improved cancer therapy in many tumor types, but no benefit of immune checkpoint therapy has been found in glioblastoma multiforme (GBM)
We used RNA-seq data from Bao and colleagues [23] and performed a supervised clustering followed by gene set enrichment analysis (GSEA) to uncover pathway activation (Fig. 1b-c)
In line with our previous results, the inflammatory response and The Janus kinase (JAK)-Signal transducer of activation (STAT) pathway was found to be significantly decreased, which has been described as the major driver for PD-L1 expression
Summary
PD-1/PD-L1 immune checkpoint inhibitors have improved cancer therapy in many tumor types, but no benefit of immune checkpoint therapy has been found in glioblastoma multiforme (GBM). We identified extended TMZ therapy as significantly inverse correlated with PD-L1 expression This led us to further investigate the role of TMZ in PD-L1 regulation, which has so far been associated with various signaling pathways, in particular the activation of the interferon-gamma (IFN) pathway [17,18,19]. JAK/STAT pathway activation via the IFNγ receptor on the surface of the tumor cell leads to an increased expression of Interferon-stimulated genes (ISGs), including PD-L1 [20]. Under physiological conditions, this mechanism contributes to immune homeostasis and limits inflammation [21]
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